Dataset Information

Lifetime Risk and Heritability of Amyotrophic Lateral Sclerosis.

ABSTRACT: Importance:Heritability describes the proportion of variance in the risk of developing a condition that is explained by genetic factors. Although amyotrophic lateral sclerosis (ALS) is known to have a complex genetic origin, disease heritability remains unclear. Objectives:To determine the extent of ALS heritability and assess the association of sex with disease transmission. Design, Setting, and Participants:A prospective population-based parent-offspring heritability study was conducted from January 1, 2008, to December 31, 2017 to assess ALS heritability, and was the first study to assess heritability in the context of known gene mutations of large effect. A total of 1123 incident cases of ALS, diagnosed according to the El Escorial criteria and recorded on the Irish ALS register, were identified. Ninety-two individuals were excluded (non-Irish parental origin [n?=?86] and familial ALS [n?=?6]), and 1117 patients were included in the final analysis. Main Outcomes and Measures:Annual age-specific and sex-specific standardized ALS incidence and mortality-adjusted lifetime risk were determined. Sex-specific heritability estimates were calculated for the overall study cohort, for those known to carry the C9orf72 (OMIM 614260) variant, and for those with no known genetic risk. Results:A total of 32 parent-child ALS dyads were identified during the study period. Affected offspring were younger at the onset of disease (mean age, 52.0 years; 95% CI, 48.8-55.3 years) compared with their parents (mean age, 69.6 years; 95% CI, 62.4-76.9 years; P?=?.008). Lifetime risk of developing ALS in first-degree relatives of individuals with ALS was increased compared with the general population (1.4% [32 of 2234] vs 0.3% [2.6 of 1000]; P?

SUBMITTER: Ryan M

PROVIDER: S-EPMC6646974 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Lifetime Risk and Heritability of Amyotrophic Lateral Sclerosis.

Ryan Marie M Heverin Mark M McLaughlin Russell L RL Hardiman Orla O

JAMA neurology 20191101 11

<h4>Importance</h4>Heritability describes the proportion of variance in the risk of developing a condition that is explained by genetic factors. Although amyotrophic lateral sclerosis (ALS) is known to have a complex genetic origin, disease heritability remains unclear.<h4>Objectives</h4>To determine the extent of ALS heritability and assess the association of sex with disease transmission.<h4>Design, setting, and participants</h4>A prospective population-based parent-offspring heritability stud ...[more]

PMID: 31329211

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Project description:ImportanceConsiderable advances have been made in our understanding of the genetics underlying amyotrophic lateral sclerosis (ALS). Nevertheless, for the majority of patients who receive a diagnosis of ALS, the role played by genetics is unclear. Further elucidation of the genetic architecture of this disease will help clarify the role of genetic variation in ALS populations.ObjectiveTo estimate the relative importance of genetic factors in a complex disease such as ALS by accurately quantifying heritability using genome-wide data derived from genome-wide association studies.Design, setting, and participantsWe applied the genome-wide complex trait analysis algorithm to 3 genome-wide association study data sets that were generated from ALS case-control cohorts of European ancestry to estimate the heritability of ALS. Cumulatively, these data sets contained genotype data from 1223 cases and 1591 controls that had been previously generated and are publically available on the National Center for Biotechnology Information database of genotypes and phenotypes website (http://www.ncbi.nlm.nih.gov/gap). The cohorts genotyped as part of these genome-wide association study efforts include the InCHIANTI (aging in the Chianti area) Study, the Piemonte and Valle d'Aosta Register for Amyotrophic Lateral Sclerosis, the National Institute of Neurological Disorders and Stroke Repository, and an ALS specialty clinic in Helsinki, Finland.Main outcomes and measuresA linear mixed model was used to account for all known single-nucleotide polymorphisms simultaneously and to quantify the phenotypic variance present in ostensibly outbred individuals. Variance measures were used to estimate heritability.ResultsWith our meta-analysis, which is based on genome-wide genotyping data, we estimated the overall heritability of ALS to be approximately 21.0% (95% CI, 17.1-24.9) (SE = 2.0%), indicating that additional genetic variation influencing risk of ALS loci remains to be identified. Furthermore, we identified 17 regions of the genome that display significantly high heritability estimates. Eleven of these regions represent novel candidate regions for ALS risk.Conclusions and relevanceWe found the heritability of ALS to be significantly higher than previously reported. We also identified multiple, novel genomic regions that we hypothesize may contain causative risk variants that influence susceptibility to ALS.

Project description:ObjectiveTo evaluate the metabolic correlates of lifetime sport practice in ALS through brain 18F-FDG-PET.Methods131 patients completed a questionnaire about lifetime exposures, including physical activity related to sports, hobbies and occupations, and underwent brain 18F-FDG-PET. Exposure to sports was expressed as MET (Metabolic Equivalent of Task). We considered only regular practice (at least 2 h/week, for at least three months). We compared brain metabolism between two groups: subjects who did not report regular sport practice during life (N-group) and patients who did (Y-group). The resulting significant clusters were used in each group as seed regions in an interregional correlation analysis (IRCA) to evaluate the impact of lifetime sport practice on brain networks typically involved by the neurodegenerative process of ALS. Each group was compared to healthy controls (HC, n = 40).ResultsWe found a significant, relative cerebellar hypermetabolism in the N-group compared to the Y-group. The metabolism of such cerebellar cluster resulted correlated to more significant and widespread metabolic changes in areas known to be affected by ALS (i.e. frontotemporal regions and corticospinal tracts) in the N-group as compared to the Y-group, despite the same level of disability as expressed by the ALS FRS-R. Such findings resulted independent of age, sex, site of onset (bulbar/spinal), presence/absence of C9ORF72 expansion, cognitive status and physical activity related to hobbies and occupations. When compared to HC, the N-group showed more widespread metabolic changes than the Y-group in cortical regions known to be relatively hypometabolic in ALS patients as compared to HC.ConclusionsWe hypothesize that patients of the N-group might cope better with the neurodegenerative process, since they show more widespread metabolic changes as compared to the Y-group, despite the same level of disability. Nevertheless, further studies are necessary to corroborate this hypothesis.

Dataset Information

Lifetime Risk and Heritability of Amyotrophic Lateral Sclerosis.

Publications

Lifetime Risk and Heritability of Amyotrophic Lateral Sclerosis.

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